ES2290114T3 - SYNTHETIC PROCEDURE OF AN INTERMEDIARY OF ECTEINASCIDINE AND FTALASCIDIN COMPOUNDS. - Google Patents

Abstract

A process for preparing an intermediate of ecteinascidin 743, comprising the steps of: (a) combination of amino lactone 4: with an acylating reagent prepared from compound 3b: to form the coupled product 6: (b) treatment of compound 6 with an allyl bromide to give amide 7: (c) reduction of the lactone compound 7 to the corresponding lactol, compound 8: (d) distillation of compound 8 to compound 9: (e) cyclization of compound 9 to compound 10: ( f) reduction of the lactam in compound 10 to the corresponding cyclic amine which, when exposed to HCN, provides the pentacyclic amino nitrile, compound 5:

Description

Synthetic procedure of an intermediary of compounds of ecteinascidin and phthalascidins.

Background of the invention

Ecteinascidin 743 (1, Et 743) is a highly potent marine antitumor agent 1 that has now been studied in various clinics in human patients 2. Because the compound is not sufficiently affordable from its natural source, the tuned Ecteinascidia turbinata , is being produced by the fully synthetic route of US Patent 5721362, 19963 which describes a synthetic process for the production of Ecteinascidin compounds and related structures, which include saframycins.

More recently, it has been found that a structural analogue of Et 473, compound 2 (phthalascidin, Pt 650) presents antitumor activity essentially indistinguishable from 1. 4

one

Both 1 and 2 are synthesized from the structural blocks 3 and 4 3 through an intermediary common pentacyclic, 5.

2

The synthesis of 5 was originally carried out 3 from structural blocks 3a and 4 in six stages with an overall yield of 35% (average performance of each stage of approximately 84%). Since it could be carried out industrial synthesis of 1 and / or 2 economically on a scale of many  kilograms, the authors of the present invention have investigated to find a more effective and reproducible alternative way from 2 and 3 to 5.

Compendium of the invention

An embodiment of the present invention it refers, according to this, to a new synthetic procedure for the preparation of intermediate 5 which is easier to carry out that the original and proceeding from 3b3 + 4 to 5 in six stages with a total yield of 57% (average performance per stage of about 92%). The preferred procedure for the synthesis of pentacycle 5 is summarized in Scheme 1. 5

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Scheme one

3

The second preferred embodiment of the The present invention involves a new synthetic process for convert the pentacyclic compound 5 to phthalascidin 2, which runs smoothly and with excellent performance (performance average per stage 90.8%. This procedure is represented in the Next Scheme 2.

Scheme 2

4

Detailed description of the embodiments preferred

As illustrated in the previous Scheme 1, add an azeotropically dried solution of amino drop by drop lactone 4 (D 7 H 8 -THF) in THF at 0 ° C with a acylating reagent prepared from 3b3 acid (1.03 equivalent), 1-hydroxy-7-azabenzothiazole (HOAT, 1.8 equivalents, hexafluorophosphate 2-Chloro-1,3-dimethylimidazolidinium  (CIP, 1.03 equivalents) and triethylamine (2.06 equivalents) in CH 2 Cl 2 solution at 0 ° C. 6

The coupling of product 6, which had been obtained by extraction, underwent alilation without further purification by treatment in DMF solution at 23 ° C with an excess of allyl bromide and 1.09 equivalents of Cs2CO3 for give amide 7 with 81% overall yield from 3rd and 4th after  of instant chromatography on silica gel.

Selective reduction of lactone function of 7 to the corresponding lactol (8) was carried out by reaction with 1.1 equivalent of lithium hydride and diethoxyaluminium (LiAlH 2 (OEt) 2) in ether at -78 ° C for 15 minutes with a yield of 95% 7.8. The de-silylation from 8 to 9 and cyclisation of 9 (without purification) using 0.6M triflic acid in H 2 O-CF 3 CH 2 OH 3: 2 at 45 ° C for 7 hours produced the pentacyclic product 10 in overall yield of 89% from 8.

Finally, the lactam function of 10 could be cleanly reduce by treatment with 4 equivalents of LiAlH 2 (OEt) 2 in THF at 0 ° C for 35 minutes to the corresponding cyclic amine that when exposed to HCN gave the pentacyclic amino nitrile 5 with 87% overall yield at from 10 after flash chromatography on gel silica. 9

The synthesis of 5 that is represented in the Scheme 1 and described above is advantageous with respect to the synthetic route originally used3 not only because the performance overall is substantially higher (57% vs. 35%), but also for the simplicity and reproducibility of the individual stages, especially the amide coupling (2 a + 3 → 6) and the internal Pictet-Spengler internal cyclization (9-10). In addition, no difficulties have been found in product purification or scale increase.

A critical element for the good outcome of the sequence shown in Scheme 1 has been the high efficiency and selectivity of LiAlH2 (OEt) 2 for both reduction stages: 8 → 9 and 10 → 5, which suggests that this reagent can be used with advantage in the synthesis more often than before.

In Scheme 2, the pentacyclic trialcohol 5 is first became phenolic monotriflate 11 (stage no shown) by treatment with 1.1 equivalents of PhNTf2 (McMurry reagent), 2 equivalents of Et3N and 0.2 equivalents of 4-dimethyl-aminopyridine in CH 2 Cl 2 at -30 ° C for 38 hours (74%). The conversion of 11 to the ether mono-t-butyldimethylsilyl (TBS) 12 and etherification with methoxymethyl chloride (MOMCl) produced 23 with high performance.

The excision of the groups N-allyloxycarbonyl and O-allyl in 13 gave the secondary amine 14 (94%) that was mixed in N to give 15 and was mixed in C to give 16. Acetylation of phenol 16 produced the corresponding acetate 17 which when alcohol was distilled primary 18. Mitsunobu displacement of the primary hydroxyl of 18 produced phthalimide 19 which in the split catalyzed by methoxymethyl ether acid provided phthalascidin 2 pure.

Although the original synthetic route to Et 743 (1) had proved acceptable for large-scale synthesis, it is expect the improved procedure described here to be even more useful as a new route to phthalascidin (2) .4. The one who phthalascidin is more stable than ecteinascidin 743 and considerably easier to obtain may be proof that it is A more practical therapeutic agent.

The present invention will be further illustrated by reference to the following examples that will help in understanding of the present invention, but not to be considered as Limitations of it. All percentages given here, to Unless otherwise specified, they are percentages by weight. All temperatures are expressed in degrees Celsius.

Example 1

5

The acid (224 mg, 0.400 mmol) was dissolved in distilled acetic acid (5.0 ml) and 0.2N HCl 10 (1.5 ml) and heated to 110 ° C. After 5.5 hours, the reaction was concentrated at vacuum and dried by repeated azeotropic concentration in vacuo with toluene (3 x 10 ml) and dissolved in DMF (1.0 ml). They were added tert-butyldimethylsilyl chloride (304 mg, 2.03 mmol) and imidazole (152 mg, 2.24 mmol) as solids and the mixture stirred at 23 ° C for 2 hours. The reaction was quenched with acid. acetic-water 2: 1 (1.5 ml) and stirred for 30 minutes The reaction was poured into 0.5 aqueous oxalic acid. M (100 ml) and extracted with acetate ethyl hexane 3: 7 (2 x 100 ml). Organic layers combined were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated under vacuum The residue was purified by flash chromatography on column (100 ml, silica gel, acetate gradient 1: 1 ethyl hexane to 0.1% acetic acid -acetate ethyl) to reach the desired product as a viscous oil substantially pure transparent (204.6 mg, 95%)

R f 0.10 (ethyl acetate); 1 H NMR (400 MHz, CDCl 3) δ 10.25 (s width, 1H), 6.32 (s, 2H), 5.90 (ddt, J = 17.0, 10.6, 5.4 Hz, 1H), 5.28 (d, J = 17.1 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H, 5.11 (d, J = 8.0Hz, 1H), 4.61-4.57 (m, 1H), 4.55 (d, J = 5.5 Hz, 2H), 3.70 (s, 3H), 3.04 (dd, J = 14.0, 5.1 Hz, 1H), 2.93 (dd, J = 14.0, 6.4 Hz, 1H), 0.99 (s, 18H), 0.15 (s, 12H);

NMR - 13 C (101 MHz, CDCl 3) δ 176.3, 155.7, 149.9, 142.2, 132.5, 130.5, 118.0, 115.6, 66.1, 60.0, 54.5, 37.2, 25.8, 18.4, -4.6;

FTIR (net) 3438 (m), 3331 (m), 3088 (m v width), 2956 (s), 2931 (s), 2894 (s), 2863 (s), 1719 (s), 1578 (s), 1496 (s), 1435 (s) 1361 (s), 1253 (s), 1231 (s), 1093 (s), 1010 (m), 938 (w), 831 (s) cm -1;

HPLC chromatography analysis performed after obtaining the derivative using diazomethane to produce the methyl ester (ChiralPak AD, 1% isopropanol in hexane, flow rate 1.0 ml / min, λ = 226 nm), 96% ee, R T = 11.1 minutes (major), 9.2 minutes (minor);

HRMS (FAB (rapid atomic bombardment), [m + H] / z Calculated for C 26 H 46 O 7 NSi 2: 540.2813, found 5402823;

[α] 23 D + 18.8 ° (c 1.0, methylene chloride).

Example 2

6

The amine was dried (100.0 mg, 0.380 mmol) by azeotropic concentration in vacuo with THF-toluene 2: 3 (5 ml) and dissolved in THF (1.5 ml) and cooled to 0 ° C. In a different flask, the acid was dried (211.7 mg, 0.392 mmol) and 1-hydroxy-7-azobenzotriazole (58.8 mg, 0.410 mmol) by vacuum azeotropic concentration with THF-toluene 2: 3 (5 ml) and dissolved in methylene (1.5 ml). To this flask was added hexafluorophosphate of 2-Chloro-1,3-dimethylimidazolidinium (109.3 mg, 0.392 mmol) as a solid and triethylamine (109 µl 0782 mmol) with syringe to obtain a solution dark yellow transparent. This mixture was stirred at 23 ° C for 3 minutes and then cooled to 0 ° and introduced, with a cannula, into the flask containing an amine. Methylene chloride was used (1.5 ml) to transfer what was left in the flask. He stirred the golden color solution at 0 ° C for 18 hours, heated to 23 ° C and stirred 6 more hours. The reaction was diluted with ethyl acetate. (6 ml) and partially concentrated in vacuo to remove chloride Methylene The solution was poured into 0.5 M aqueous acetic acid. (100 ml), extracted with ethyl acetate-hexane 3: 7 (100 ml) and washed with saturated aqueous bicarbonate solution of sodium (100 ml). The aqueous layers were reextracted with 3: 7 ethyl acetate-hexane (100 ml) and layers The combined organics were dried over sodium sulfate, dried filtered and concentrated in vacuo to lead to a film transparent (approximately 300 mg). This residue was used without subsequent purification. The material can be purified by flash column chromatography (100 ml, silica gel, gradient 1: 3 to 2: 3 ethyl acetate-hexane), obtaining, however, only 50% yield due presumably to the decomposition promoted by the gel silica.

R f 0.36 (acetate ethyl hexane 2: 3); NMR - 1 H (400 MHz, CDCl 3) δ (mixture of carbamate retainers and amide) 6.35 (s, 1H), 6.20 (s 1H), 5.91-5.81 (m, 3H),  5.94-5.59 (m, 1.5H), 5.42 (d, J = 3.3 Hz, 0.5H), 5.30-5.03 (m, 3H), 4.74-4.63 (m, 1H), 4.60 (dd, J = 10.8, 3.1 Hz, 0.5H), 4.53 (wide s, 1M), 4.45 (d, J = 5.1 Hz, 1H), 4.36 (d, J = 10.6 Hz, 0.5H)), 4.19 (d, J = 10.6 Hz, 0.5H), 3.68 (s, 1.5H), 3.61 (s, 1H), 3.56 (d, J = 8.4 Hz, 0.5H), 3.03-2.90 (m, 3H), 2.79 (dd, J = 13.0, 4.6 Hz, 0.5H), 2.24 (d = 16.0 Hz, 0.5H), 2.06 (wide s, 3H), 099 (s, 9H), 0.91 (s, 9H), 0.15 (s, 6H);

NMR - 13 C (101 MHz, CDCl 3) δ (mixture of carbamate and amide rotamers, 169.2,  169.0, 167.9, 167.5, 155.6, 155.2, 150.1, 149.7, 146.9, 146.5, 145.1, 145.0, 142.1, 141.7, 136.8, 136.2, 132.4, 132.3, 130.7, 130.3, 117.9, 117.8, 115.5, 115.3, 11.3, 110.9, 110.5, 108.1, 107.8, 101.4, 73.0, 66.1, 65.9, 60.0, 59.9, 54.7, 52.2, 51.9, 51.0, 47.6, 43.2, 39.6, 38.5, 29.1, 27.4, 25.8, 25.7, 18.4, 18.3, 8.9, -4.56, -4.65, -4.74;

FTIR (net) 3406 (w width), 3319 (w width), 29.56 (m), 29.31 (m), 2894 (w), 2856 (m), 1725 (m), 1644 (m), 1575 (m), 1494 (m), 1463 (m), 1431 (s), 1356 (w), 1231 (s), 1356 (w), 1231 (s), 1163 (w), 1094 (s), 1044 (m) 1013 (m), 831 (s) cm -1:

HRMS (ESI) [m + H) / z calculated for C_ {39} H_ {57} O_ {11} N2 {Si} {2}: 785.3469, found 785.3469;

[α] 24 D + 20.5 ° (c 1.0, chloroform).

Example 3

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7

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The phenol (~ 300 mg, 0.380 mmol) was dried by vacuum azeotropic concentration with toluene (5 ml) and dissolved in DMF (15 ml). Allyl bromide (330 µL, 3.82 mmol) with syringe and cesium carbonate (134.7 mg, 0.413 mmoles), dried gently to the flame, vacuum as a solid and the The reaction was stirred at 23 ° C for 2 hours. The reaction was poured into water (300 ml), extracted with acetate ethyl hexane 1: 4 (2 x 150 ml), washed with chloride of saturated aqueous sodium (100 ml), dried over sodium sulfate, It was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (75 ml, silica gel, gradient 1: 4 to 3: 7 ethyl acetate-hexane to give the desired product as a transparent film substantially pure (252.9 mg, 81% in two stages). This material it was unstable to silica gel so it was critical do a quick chromatography to get the performance observed.

R f 0.47 (acetate ethyl hexane 2: 3); NMR - 1 H (400 MHz, CDCl 3) δ (mixture of carbamate and amide rotamers 6.35 (s, 1H), 6.20 (s 1H), 6.03-5.78 (m, 5H), 5.52-5.44 (m, 1.4H), 5.38-5.33 (m, 1H), 5.31-5.13 (m, 3.6), 4.73-4.59 (m, 1.4 H), 4.55 (d, J = 5.1 Hz, 1H), 4.48 (d, J = 5.1 Hz, 1H), 4.34 (d, J = 10.6 Hz, 0.6 H), 4.24-4.04 (m, 3H), 3.68 (s, 1.5H), 3.60 (s, 1.5H), 3.54 (d, J = 8.8 Hz, 0.4 H), 3.15-2.90 (m, 2.6 H), 2.77 (dd, J = 12.8, 4.8 Hz, 0.6 H), 2.34 (m, 0.4H), 2.12 (s, 1.5H), 2.09 (s, 1H), 0.99 (s, 9H), 0.92 (s, 9H), 0.16 (s, 6H); 0.07 (s, 3H), 0.05 (s, 3H);

NMR - 13 C (101 MHz, CDCl 3) δ (mixture of carbamate and amide rotamers, 169.2,  169.0, 168.8, 167.4, 167.1, 155.5, 155.1, 150.2, 150.0, 149.8, 145.5, 145.3, 142.2 141.9, 139.2, 138.8, 133.4, 133.2, 132.4, 130.6, 130.2, 118.3, 118.0, 117.9, 117.8 117.7, 117.2, 115.5, 115.2, 114.3, 113.9, 111.1, 110.9, 101.8, 101.7, 73.8. 73.7, 72.8, 66.1, 65.9, 60.04, 59.99, 54.9, 52.1, 51.9, 51.1, 47.7, 43.3, 39.8, 38.5, 29.6, 27.9, 25.8, 25.7, 18.4, 18.3, 9.6, 9.4, -4.51, -4.54, -4.6, -4.7;

FTIR (net) 3306 (m), 2956 (w wide), 2931 (m), 2898 (m), 2856 (m), 1750 (m), 1719 (m), 1650 (m), 1575 (m), 1494 (m), 1431 (m), 1363 (s), 1250 (m), 1231 (m), 1163 (w), 1094 (s), 1044 (m), 1013 (m), 944 (w), 919 (w), 831 (s) cm -1:

HRMS (ESI) [m + H) / z calculated for C_ {42} H_ {61} O_ {11} N2 {Si} {2}: 825.3814, found 825.3788;

[α] 24 D + 21.7 ° (c 1.0, chloroform).

Example 4

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8

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The lactone (354.1 mg, 0.429 mmol) was dried by azeotropic concentration in vacuo with toluene (10 ml), dissolved in diethyl ether (8.0 ml) and cooled to -78 ° C in a bath of dry aceton-ice. A 0.10 M solution of LiAlH 2 (OEt) 2 (4.7 ml, 0.47 mmol) 11, drop by drop along the side of the flask over 2 minutes. The The reaction was stirred at -78 ° C for 15 minutes and then the light yellow solution in 0.1 N HCl (50 ml) at 0 ° C while He waved quickly. This solution was extracted with diethyl ether (2 at 75 ml), washed with saturated aqueous sodium chloride (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. He residue was purified by flash column chromatography (150 ml, silica gel, gradient 3: 7 to 2: 3 to 1: 1 acetate ethyl-hexane) to reach the desired product as substantially pure transparent film (339.0 mg, 95%.

R f 0.20 (acetate ethyl hexane 2: 3); NMR - 1 H (400 MHz, CDCl 3) δ (mixture of anomers, carbamate rotamers and amide) 6.43 (s, 0.2H), 6.37 (s, 0.2H), 6.16 (s, 1.4H), 6.15 (s, 0.2H), 6.05-5.80 (m, 4.4H), 5.82-5.59 (m, 1.2 H), 5.41-5.14 (m, 3.8H), 5.07-4.95 (m, 1.5H), 4.85-4.76 (m, 1.6H), 4.61-4.46 (m, 2.2H), 4.26-4.41 (m, 3.8H), 4.10-3.75 (m, 0.5H), 3.68 (s, 0.3H), 3.66 (s, 0.3H), 3.63 (s, 2.4H), 3.37 (d, J = 11.0 Hz, 0.8H, 3.33-2.94 (m, 07H), 2.90-2.65 (m, 2.8H), 2.35 (dd, J = 17.7, 7.5 Hz, 0.7H), 2.12 (s, 0.3H), 2.11 (s, 0.3H), 2.09 (s, 2.4H), 1.05 (s, 4.5H), 0.92 (s, 13.5H), 0.16 (s, 3H), 0.07 (s, 4.5H), 0.04 (s, 4.5H);

NMR - 13 C (101 MHz, CDCl 3) δ (mixture of anomers, carbamate rotamers and amide) 169.8, 156.1, 149.6, 149.2, 144.6, 141.7, 138.3, 133.8, 132.2, 130.2, 118.9, 118.0, 116.7, 115.1, 113.4, 112.5, 101.3, 93.4,  73.2, 66.2, 62.4, 60.1, 53.6, 51.4, 44.6, 38.5, 26.5, 25.9, 25.8, 18.5, 18.3, 9.5, -4.56, -4.59;

FTIR (net) 3406 (wide m), 3325 (wide m), 2956 (m), 2931 (m), 2894 (m), 2856 (m), 1714 (m), 1644 (m), 1578 (m), 1496 (m), 1433 (s), 1360 (m), 1255 (m), 1234 (m), 1095 (s), 1044 (m), 1013 (s), 941 (w), 830 (s) cm -1:

HRMS (ESI) [m + H) / z calculated for C_ {42} H_ {63} O_ {11} N2 {Si} {2}: 827.3970, found 827.4009;

[α] 25 D -1.5 ° (c 1.0, chloroform).

Example 5

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9

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Lactol was dissolved (316.3 mg, 0.382 mmol) in nitrogen-purged methanol (3.8 ml). Fluoride was added anhydrous potassium (110.3 mg, 1.90 mmol) as a solid and the vessel was pumped / purged with nitrogen. The reaction was stirred at 23 ° C for 30 minutes and the mixture, light pink, was diluted with toluene (5 ml) and concentrated in vacuo. The residue was dissolved in 2,2,2-trifluoroethanol (15 ml) purged with nitrogen and butylated hydroxytoluene (4.3 mg, 0.02 mmol) was added Like a solid The flask was charged with trifluorometasulfonic acid 1.0 M aqueous 12 M (23 ml) and the vessel was pumped / purged from New with nitrogen. The solution was stirred at 45 ° C in a bath of oil for 7 hours. The mixture was partially concentrated at empty, to separate the alcohol, and poured into sodium chloride 80% saturated aqueous (100 ml), extracted with ethyl acetate (2 x 100 ml), washed with saturated aqueous sodium chloride (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. He residue was purified by flash column chromatography (100 ml, silica gel, methanol-methylene chloride 5:95) to reach the desired product as a white solid substantially pure (198.5 mg, 89%). Crystals were obtained in Toluene.

Melting point (M.p.) 130 ° C (dec.); R_ {f} 0.11 (methanol-methylene chloride 5:95); 1 H NMR (400 MHz, acetone-d_ {3} δ (mixture of rotamers of carbamate) 8.34 (wide s, 1H), 8.32 (wide s, 1H), 6.31 (d, J = 4.4 Hz, 1H), 6.14 (m, 1H), 5.97 (s, 1H), 5.97-5.90 (m, 1H), 5.90 (s, 1H), 5.68 (m, 1H), 5.42-5.37 (m, 2H), 5.31-5.22 (m, 2H), 5.18-5.12 (m, 1H), 4.85 (d, J = 6.6 Hz, 1H), 4.65-4.55 (m, 2H), 4.38-4.34 (m, 1H), 4.26-4.22 (m, 1H), 3.89-3.86 (m, 1H), 3.77 (s, 3H), 3.71 (m, 1H), 3.57 (d, J = 15.0 Hz, 1H), 3.48-3.43 (m, 1H), 3.25-3.13 (m, 2H), 3.00 (d, J = 16.8 Hz, 1H), 2.34 (m, 1H), 2.11 (s, 3H);

NMR - 13 C (101 MHz, acetone-d_ {6} δ (mixture of rotamers of carbamate) 169.4, 169.2, 153.8, 150.6, 149.3, 148.2, 148.0, 145.5, 141.0, 135.1, 134.5, 133.9, 130.2, 130.1, 122.4, 117.9, 117.8, 117.7, 117.5, 114.2, 112.7, 111.0, 110.8, 108.4, 108.3, 102.1, 75.4, 66.74, 66.69, 65.6, 61.6, 61.2, 60.9, 54.3, 53.5, 52.9, 50.1, 49.3, 34.1, 33.6, 27.5, 9.7;

FTIR (KBr) 3400 (wide s), 2944 (wide m), 2881 (m), 1700 (s), 1639 (s), 1501 (w), 1463 (s), 1435 (s), 1356 (m), 1320 (m), 1288 (m), 1269 (m), 1238 (m), 1213 (m), 1166 (m), 1102 (s), 1065 (s, 1030 (m), 999 (m), 938 (m), 807 (w) cm -1:

HRMS (ESI) [m + H) / z calculated from C 33 H 33 O 10 N 2: 581.2135, found 581.2112;

[α] 25 D -27.2 ° (c 1.0, methanol).

Example 6

10

The amide (198.0 mg 0.341 mmol) was dried by azeotropic concentration in vacuo with toluene (10 ml), dissolved in THF (10 ml) and cooled to 0 ° C. It was added, drop by drop along 10 minutes, a 0.20 M solution of LiAlH 2 (OEt) 2 (6.8 ml, 1.36 mmol) 13. The reaction was stirred at 0 ° C for 35 minutes to give the carbinolamine, R f 0.59 (acetate ethyl hexane 4: 1). Acetic acid was added first (425 µL, 7.44 mmol) to quench the reaction. Later added 4.8 M aqueous potassium cyanide (425 µL, 2.04 mmol), anhydrous sodium sulfate (2.5 g, 17.6 mmol) and Celite® (6 ml) to affect the conversion to amino. nitrile and for precipitate aluminum salts. Bubbling was observed and after 5 minutes, the reaction was heated to 23 ° C and stirred for 7 hours. The suspension was filtered through Celite® pad, eluting with ethyl acetate (100 ml). This solution was concentrated. under vacuum and purified by flash column chromatography (100 ml, silica gel, 2: 1 ethyl acetate-hexane) to give the desired product as a white foam substantially pure (175.6 mg, 87%).

R f 0.31 (acetate ethyl hexane 4: 1); NMR - 1 H (400 MHz, CDCl 3) δ (mixture of carbamate rotamers) 6.43 (wide s, 0.6H), 6.26 (s, 0.4H), 6.24 (s, 0.6H), 6.20 (s, 0.4H), 6.07-6.00 (m, 1H), 5: 97-5.82 (m, 4H), 5.61 (s, 0.6H), 5.52 (s, 04H), 5.37-5.17 (m, 3H), 4.90 (d, J = 7.8 Hz, 0.4H), 4.84 (d, J = 8.3 Hz, 0.6 H), 4.73-4.60 (m, 2H), 4.16-4.08 (m, 2.6H), 3.97-3.94 (m, 1.4H), 3.77 (s, 1.2H), 3.68-3.61 (m, 1H), 3.62 (s, 1.8H), 3.49-3.36 (m, 1H), 3.29-3.19 (m, 3H), 2.76-2.69 (m, 1H), 2.11 (s, 1.8H), 2.08 (s, 1.2H), 2.00-1.83 (m, 2H);

NMR - 13 C (101 MHz, CDCl 3) δ (mixture of carbamate rotamers) 154.3, 153.8, 148.4, 148.34, 148.26, 146.2, 145.9, 144.3, 138.8, 133.62, 133.56, 132.7, 132.2, 130.7, 130.3, 120.5, 120.3, 117.9, 117.8, 117.4, 117.2, 116.3, 112.6, 112.5, 112.1, 111.9, 107.2, 106.4, 101.1, 74.5, 74.0, 66.7, 66.5, 64.5, 64.3, 60.8, 60.5, 59.1, 58.9, 58.0, 56.7, 56.6, 49.9, 49.4, 48.9, 48.7, 31.2, 30.5, 29.7, 25.9, 9.43, 9.35;

FTIR (net) 3369 (m wide), 2931 (m wide), 1688 (m), 1500 (w), 1463 (m), 1431 (s), 1375 (m), 1325 (m), 1294 (m), 1269 (m), 1106 (s), 1063 (m), 994 (m), 956 (w), cm -1:

HRMS (ESI) [m + H) / z calculated for C 31 H 34 O 9 N 3: 592.2295, found 592.2316;

[α] 25 D + 30.4 ° (c 1.0, chloroform).

Example 7

eleven

The phenol was dried (170 mg, 0.287 mmol) by azeotropic concentration in vacuo with toluene (100 ml) and dissolved in methylene chloride (3.0 ml). Triethylamine was added (80 µL, 0.574 mmol) and 4-dimethylaminopyridine (7.0 mg, 0.0574 mmol) and the solution was cooled to -30 ° C in a bath of dry ice-acetonitrile. Was added N-phenyltrifluoromethanesulfonimide (113.5 mg 0.318 mmol) as a solid and the reaction was stirred at -30 ° C in a bath Cryobath® for 38 hours. The mixture was poured into bicarbonate saturated aqueous sodium-aqueous sodium chloride saturated 1: 1 (100 ml), extracted with methylene chloride (2x75 ml), dried over sodium sulfate, filtered and concentrated to empty. The residue was purified by flash chromatography on column (100 ml, silica gel, gradient 2: 3 to 3: 4 acetate ethyl hexane) to give the desired product as substantially pure transparent film (153.4 mg, 74%).

R f 0.18 (acetate ethyl hexane 2: 3); NMR - 1 H (400 MHz, CDCl 3) δ (mixture of carbamate rotamers) 7.16 (s 0.6H), 6.63 (s, 0.4H), 6.60 (s, 0.6H), 6.45 (s, 0.4H), 6.08-5.86 (m, 4H), 5.74 (m, 0.6H), 5.59 (m, 0.4H), 5.40-5.16 (m, 4H), 4.96-4.89 (m, 1H), 4.74-4.60 (m, 3H), 4.26 (m, 1H), 4.19-4.15 (m. 2H), 4.00 (m, 1H), 3.89 (s, 1.2H), 3.83 (s, 1.8H), 3.66-3.64 (m, 1H), 3.39-3.24 (m, 4H), 2.91-2.83 (m, 1H), 2.11 (s, 1.2H), 2.05 (s, 1.8H), 1.86-1.78 (m, 1 HOUR);

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NMR - 13 C (101 MHz, CDCl 3) δ (mixture of carbamate rotamers) 154.0, 153.9 148.6, 148.4, 147.3, 146.6, 144, 7 144.5, 141.3, 141.0, 139.1, 138.9, 136.9, 136.7, 133.7, 132.2, 132.1, 131.6, 129.4, 127 , 0, 123.0, 121.5, 121.3, 119.9, 118.5 (q, J = 321 Hz, CF 3), 118.2, 117.7, 117.6, 117, 4, 116.3, 116.1, 112.6, 112.3, 112.1, 112.0, 101.3, 101.2, 74.5, 66.9, 66.7, 65.7, 65.5, 62.0, 61.9, 59.54, 59.48, 58.6, 56.5, 49.8, 49.3, 49.0, 48.4, 31.0, 30, 4, 26.1, 26.0, 9.5,
9.4;

19 F NMR (376 MHz, BF 3. OEt 2 conventional setting at -153.0 ppm, CDCl 3) δ (mixture of carbamate rotamers) -74.02, -74.01;

FTIR (net) 3325 (w wide), 2949 (w wide), 1688 (m), 1588 (w), 1500 (m), 1425 (s), 1319 (m), 1288 (m), 1256 (m), 1213 (s), 1138 (s), 1106 (m), 1038 (m), 988 (m), 875 (w), cm -1:

HRMS (ESI) [m + H) / z calculated for C_ {32} H_ {33} O_ {11} N_ {3} SF_ {3}: 724.1788 found 724.1803;

[α] 26 D + 34.3 ° (c 1.0, chloroform).

Footnotes

The following publications provide background information and are incorporated here both as reference.

(1) The pioneering research in this area is due to Professor Kenneth L. Rinehart and his group. See (a) Rinehart ., KL; Shield , LS. in Topics in Pharmaceutical Sciences , eds. Breimer, DD; Crommelin, DJA; Midha, KK (Amsterdam Medical Press, Noordwijk, The Netherlands), 1989 , page 613. (b) Rinehart , KL; Holt , TG; Fregeau , NL; Keifer , PA; Wilson , GR; Perun , TJ Jr; Sakai , R .; Thompson AG; Stroh , JG; Shield , LS Seigler , DS: Li . LH Martin . DG; Grimmelikhuidjzen , GJP; Gäde , GJ Nat. Prod . 1990 , 53, 771. (c) Rinehart , KL; Sakai , R; Holt , TG; Fregeau , NL Perun TJ, Jr; Seigler , DS; Wilson , GR; Shield , LS Pure Appl. Chem 1990 , 62 1227. (d) Reinehart KL; Holt TG; Fregeau , NL; Stroh , JG; Keifer , PA; Sun , F .; Li , LL.H .; Martin , DG J. Org. Chem 1990 , 55, 4512. (e) Wright , AE; Forleo , DA; Gunawardana , GP; Gunasekera , SP; Koehn , FE; McConnell , OJ, J. Org. Chem 1990 , 55, 1990 , 55, 4508. (f) Sakai , R .; Rinehat , KL; Guan , Y .; Wang , H. J. Proc. Natl Acad. Sci USA 1992 , 89, 11456.

(2) (a) Business Week, September 13, 1999, p. 22. (b) Science 1994 , 266, 1324.

(3) Corey , EJ; Gin , DY; Kania , RJAm. Chem. Soc . 1996 , 118, 9202.

(4) Martinez EJ; Owa , T .; Schreiber , SL; Corey , EJ Proc. Natl Acad. Scci USA 1999 , 96, 3496.

(5) See Myers , AG; Kung DW, J. Am. Chem. Soc . 1999 , 121, 10828 for a different method of synthesis of structures such as 5.

(6) For the carboxylic acid-amine coupling methodology using CIP, see: (a) Akaji , K .; Kuriyama , N. Kimura , T .; Fujiwara , Y; Kiso , and, Tetrahedron Lett . 1992 , 33, 3177, 33, 3177. (b) Akaji , K .; Kuriyama , N .; Kiso , Y. Tetrahedron Lett . 1944 , 35, 3315. (c) Akaji , K. Kuriyama , N .; Kiso , YJ Org. Chem 1996 , 61, 3350.

(7) LiAlH2 (OEt) 2 reagent was prepared by adding a 1.0M solution of LiAlH4 in ether to a solution of 1 equivalent of 0 ° C ethyl acetate and stirring at 0 ° C for 2 hours immediately before use; see; Brown , HC; Tsukamoto , A. J. Am. Chem. Soc . 1964 , 86, 1089.

(8) For a general review on lactone reduction see: (a) Brown , HC: Kishnamurthy , S., Tetrahedron , 1979 , 35, 567. (b) Cha , JS Org. Prep. Proc. Int . 1989 , 21 (4), 451. (c) Seyden-Penne , J. Reduction by aluminohydrides and borohydrides in Organic Synthesis ; 2nd edition; Wiley-VCH ; New York, 1997 ; Section 3.2.5.

(9) For general references on amide reduction by hydride reagents see reference (7) and also Myers , AG; Yang , BH .; Chen , H .; Gleason , JL J. Am. Chem. Soc ., 1994 , 116, 9361.

(10) Obtained in water purged by nitrogen.

(11) This reagent was obtained by adding 1.0 M solution of lithium aluminum hydride in Et 2 O (1 equivalent) to a solution of ethyl acetate (1 equivalent) in Et 2 O at 0 ° C . The mixture was then stirred at 0 ° C for 2 hours and a portion of the reagent was used for lactol reduction. Brown , HC .; Tsukamoto , A. J. Am. Chem. Soc . 1964 , 86, 1089.

(12) Obtained in water purged with nitrogen.

(13) See the reference cited in note a footer (11).

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The present invention has been described with detail, including the preferred embodiments of the same. It should be noted, however, that specialists in this technique, when considering the present description, can do modifications and / or improvements on the invention that are still within of the framework and spirit of the invention as established in The following claims.

Claims (15)

1. A procedure for preparing a ecteinascidin intermediate 743, comprising the steps from: (a) combination of amino lactone 4:

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12 with an acylating reagent prepared from the compound 3b:

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13 to form the coupled product 6:

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14

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(b) treatment of compound 6 with a bromide of allyl to give amide 7: fifteen (c) reduction of the lactone compound 7 to corresponding lactol, compound 8: 16 (d) distillation of compound 8 to compound 9: 17 (e) cyclization of compound 9 to compound 10: 18 (f) reduction of lactam in compound 10 to corresponding cyclic amine that when exposed to HCN provides the Pentacyclic amino nitrile, compound 5: 19 2. The method of claim 1, for prepare phthalascidin, which also includes the steps of (g) the conversion of the compound of formula 5 to compound of formula 11 by treatment with PhNTf2 twenty (h) conversion of compound 11 to mono ether t-butyldimethylsilyl (TBS), compound 12: twenty-one (i) etherification with methoxymethyl chloride to give compound 13: 22 (j) division of the groups 13-allylcarbonyl and 13-day O-allyl the secondary amine, compound 14:

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2. 3 (k) N-methylation of the compound 14 leading to compound 15:

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24 (l) C-methylation of the compound 15 leading to compound 16:

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25 (m) acetylation of phenol 16 leading to corresponding acetate, compound 17:

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26

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(n) desililation of compound 17 that conducts to primary alcohol, compound 18:

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27

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(o) Mitsunobu displacement of the hydroxyl Primary 18, which leads to phthalimide, compound 19:

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28

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(p) acid catalyzed cleavage of the ether methoxymethyl compound 19, generates the compound 2-phthalascidin

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29

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3. The synthetic intermediary of the procedure according to claim 1 - compound 6: 30 4. The synthetic intermediary according to method of claim 1-compound 7: 31 5. The synthetic intermediary of the procedure according to claim 1-compound 8:

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32 6. The synthetic intermediary of the procedure according to claim 1 - compound 9:

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33

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7. The synthetic intermediary of the procedure according to claim 1 - compound 10: 3. 4 8. The synthetic intermediary of the procedure according to claim 2 - compound 12:

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35

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9. The synthetic intermediary of the procedure of claim 2 - compound 13:

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36

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10. The synthetic intermediary of process according to claim 2 - compound 14:

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37

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11. The synthetic intermediary of the procedure according to claim 2 - compound 15:

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38

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12. The synthetic intermediary of the procedure according to claim 2 - compound 16:

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39

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13. The synthetic intermediary of the procedure according to claim 2 - compound 17:

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40

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14. The synthetic intermediary of the procedure according to claim 2 - compound 18:

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41

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15. The synthetic intermediary of the procedure of claim 2 - compound 19: 42